Molecular Genetic Studies on the Physiological Function and Disorders of DNA Methylation

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Methylation of CpG dinucleotides plays a central role in the epigenetic genome regulation, and its defects cause congenital disorders and cancers. We have studied the functions and disorders of DNA methyltransferases (DNMTs) and methyl-CpG-binding proteins (MBD proteins) and found the followings. 1.By knocking out mouse DNMT3A, a de novo-type. DNMT, in a germline-specific manner, we found that this enzyme is essential for paternal and maternal imprinting. 2.Enzymatic properties and target specificities of DNMT3A and DNMT3B were determined. 3.New mutations of DNMT3B were identified in Japanese families with ICE syndrome. We also found an ICE case with no mutation in DNMT3B, which suggests the heterogeneity of the disease. 4.We reported that paternal disomy 14 is a new imprinting-related disorder characterized by bell-shaped chest and wavy ribs. 5.We found that MBD1 represses transcription and forms repressive chromatin through two independent pathways: 1) one mediated by a complex formed with a transcriptional mediator MCAF/AM and a histone methyltransferase SETDB1/ESET; 2) the other involving a histone methyltransferase Suv39, a histone deacetylase HDAC1/2 and a heterochromatin protein HP1. 6.The tertiary structure of the DNA binding domain of MBD1 complexed with a. methylated-CpG-containing DNA molecule was determined. 7.The mutations of McCP2 causing Rett syndrome were found to impair its ability to repress transcription and to form repressive chromatin. 8.We reported that MBD1 promotes base excision repair in cooperation with a methylated-purine DNA glycosylase. All together, our findings have greatly increased our knowledge on the mechanisms of DNA methylation and transcriptional repression through it and the pathology of DNA methylation-associated disorders.